Sarajevo (Bosnia Hercegivina) Monday June :30-16:15. PET/CT in Lymphoma

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1 Sarajevo (Bosnia Hercegivina) Monday June :30-16:15 PET/CT in Lymphoma FDG-avidity Staging (nodal & extra nodal) Response evaluation Early assessment during treatment / interim (ipet) Remission assessment at the end of treatment The Deauville 5 point scale (5PS) Helle W Hendel

2 Lymphoma Subtypes differ in molecular characteristics biologic behavior aggressive indolent The WHO histologic classification morphologic immunohistochemical genetic features The most important factors for therapy and prognosis histologic subtype extent of disease Coloured scanning electron micrograph of dividing Hodgkin's cells taken from the pleural effusions of a 55 year old, male patient with "mixed cellularity Hodgkin disease

3 Limitations of conventional imaging Conventional imaging is based on extent and size Limitations Benign lymph node enlargement Malignant small lymph nodes Limited detection extra nodal disease in spleen, liver, and bone marrow Equivocal lesions require additional imaging or biopsy

4 FDG-avidity (WHO classification) METHODS: The reports from FDG PET/CT studies performed in a single center for staging of 1,093 patients with newly diagnosed Hodgkin disease and non-hodgkin lymphoma were reviewed for the presence of FDG avidity. 766 patients with a histopathologic diagnosis verified according to the WHO classification were included in the final analysis. Weiler-Sagie M et al FDG Avidity in Lymphoma Readdressed: A Study of 766 Patients JNM 2010

5 FDG-avidity METHODS (cont): FDG avidity was defined as the presence of at least 1 focus of FDG uptake reported as a disease site.. Non avidity was defined as disease proven by clinical examination, conventional imaging modalities, and histopathology with no F-FDG uptake in any of the involved sites Weiler-Sagie M et al FDG Avidity in Lymphoma Readdressed: A Study of 766 Patients JNM 2010

6 FDG-avidity FDG-avidity is lower in indolent disease (83%) than in aggressive disease (97%). Indolent subtypes (eg. plasmacytoma, follicular lymphoma) are FDG-avid Aggressive (enteropathy-type T-cell lymphoma) has low FDG-uptake * *

7 Lymphoma Common radiographic features of lymphoma Homogeneous lymph node lesions Continuous or scattered whole body distribution of nodal lesions. Splenomegaly and intra spleen lesions, Non-destructive expansion of extranodal lesions, invasive progression without occlusion of the adjacent gastrointestinal tract or vessels Renal cortical lesions (rare in other malignancies) In particular, the formation of multiple lymph node lesions in distant sites is one of the characteristics differentiating lymphoma from lymph node metastasis of common cancer, FDG-PET allows whole-body scanning which is a strong point in its favour.

8 Example of renal cortical lesion

9 Staging HL and aggresive NHL In both HL and aggresive NHL, FDG-PET detects more disease sites (nodal and especially extranodal), than conventional imaging, resulting in a higher sensitivity, leading to significant upward stage migration.

10 Staging HL and aggresive NHL FDG PET for staging of lymphoma From: Baba S et al. Impact of FDG-PET/CT in the management of lymphoma. Ann Nucl Med (2011) 25:701-16

11 Improved accuracy In the past, most clinical studies on PET have focused on diagnostic accuracy or changes in management, without briding the gab to patient-relevant outcomes Improved patient-relevant outcome

12 Staging of bone marrow PET seems to be at least as sensitive as blind bone marrow biopsy in HL and aggressive NHL and may eliminate the need for bone marrow biopsy in the primary staging FDG-PET Sagital view

13 Bone marrow involvement in HL * 5 BMB positive; advanced stage, abnormal PET 12 cases missed by BMB PET-CT upstaged 9.7% of patients BMB upstaged one patient (stage IV PET-CT) BMB did not alter clinical management 93 HL 5 year retrospective data Reactive= diffuse symmetrical uptake Positive = Patchy focal uptake * Conclusion: BMB has little or nothing to offer staging HL in the PET-CT era Consider wether FDG-positive truely represents bone/bone marrow involvement: - FDG avid disease - Correlation with advanced stage (CT, anamia, raised LDH, B-symptoms) El-Galaby TC et al. routine bone marrow bippsy has little or no therapeutic consequence for positron emission tomography/computed tomograpyhy-staged treatment-naïve patients with Hodgkin lymphoma J Clin Oncol 2012;30:

14 Bone marrow involvement DLBCL DEFINITION OF NEGATIVE PET TARGETED MR INITIAL FALSE NEGATIVE BMB RESPONSE TO TREATMENT J Nucl Med 2013; 54:

15 Bone marrow involvement DLBCL Criteria for BMI in the study: Targeted MR imaging Guided biopsy Disappearance of bone marrow uptake concomitant with reduced uptake in other 18F-FDG avid lymphoma lesions on PET/CT monitoring N = 133 PET/CT+ (32) PET/CT- (101) BMB+ (8) BMB- (125) PET/CT vs BMB Sensitivity : 93.9 vs 24.2 NPV:89% vs 80% Specificity and PPV: ns Among 26 patients with positive FDG PET/CT and negative BMB 11 were upstaged

16 Bone marrow involvement DLBCL PFS was higher for patients with negative BMB (A) Same pattern seen with negative FDG PET/CT (B)

17 Bone marrow involvement DLBCL NEGATIVE BMB POSITIVE BMB PET negative N = 99 PET negative N = 2 PET positive N = 26 PET positive N = 6

18 Bone marrow involvement Currently, only BMB is recommended for the evaluation of BMI in HL and Non HL BMI is usually focal The diagnostic performance of 18F-FDG PET/CT is better than BMB Bone marrow status with 18F-FDG PET/CT appears to be a better independent prognostic factor than bone marrow status with BMB in non HL

19 Staging of bone marrow PET-CT can miss low volume BM involvement (< 20% of the marrow) and co-existent low grade lymphoma in DLCBCL although this rarely affects management The sensitivity of PET for diffuse marrow involvement is limited in FL and mantle cell and most indolent lymphomas where biopsy is required for stating

20 Intracerebral lymphoma Intracerebral lymphoma often shows intense uptake, leptomeningeal disease which may be diffuse and low volume may be missed. MRI is preferred to assess suspected CNS involvement.

21 Staging of FDG-avid lymphoma FDG PET/CT is recommended in staging and at baseline for comparison in (early and) end of treatment response evaluation preferrably in clinical trials. May be used to select the best site to biopsy Focal uptake in HL and aggressive NHL is sensitive for BM involvement. MRI is the modality of choice for suspected CNS lymphoma

22 Response evaluation - general Surrogate endpoint and decision guide Tumor response serves as an important surrogate for other measures of clinical benefit such as progression-free and overall survival Tumor response also serves as an important guide in decisions regarding continuation or change of therapy In the (near) past response was based mainly on morphological criteria with a reduction in tumor size on CT as the most important factor

23 Response evaluation - general Resolution of uptake at sites of initial disease indicates metabolic response. Reduction of uptake may also indicate satisfactory response but the degree of uptake that is indicative of response is dependent on - the timing of the scan during treatment - the clinical context (prognosis, lymphoma subtype, treatment regimen) A baseline scan is considered optimal for the accuracy of subsequent response assessment

24 Response evaluation - general Early response evaluation/interim (ipet): Prediction of response to therapy End of treatment evaluation Prognostication (PFS, OS)

25 End of treatment response Residual masses After completion of therapy CT will often reveal residual masses. It is very difficult to assess whether this represents viable lymphoma, fibrotic scar tissue or necrosis in patients with otherwise clinical complete response. To perform a biopsy on all these lesions would be impractical, and even if it were done it would be too inaccurate. CRu complete remission unconfirmed

26 End of treatment response The International Harmonization Project (IHP) incorporated FDG-PET findings into the definitions of end-of-treatment response in FDG-avid lymphomas in 2007 CRu* was eliminated: CR is FDG-negative PR if FDG-positive *the cases in which the tumor remains on the image but does not change its size over 3 months without treatment

27 End of treatment response evaluation - IHP The International Harmonization Project (IHP) Interpretation Criteria 2007 *. PET-negative residual mass FDG uptake lower than the local background for lesions less than 2 cm or lower than mediastinal blood pool for lesions equal or greater than 2 cm Use: Widely accepted for end-oftreatment evaluation *Juweid et al. JCO 2007 RM is seen in 75% of HL and 30% of NHL by morphological imaging after the completion of therapy

28 End of treatment response evaluation Recommendations PET/CT is the standard of care for remission assessment in FDG-avid lymphoma Biopsy of residual metablically active tissue is advised prior to institution salvage treatment If clincial suspicion of recidual disease is low, a repeat scan could be performed in 3 months to determine if uptake has diminished.

29 End of treament response FDG-PET is standard care for remission assessment. FDG-PET distinguish between viable lymphoma and necrosis/fibrosis in residual masses (CT-scan) after treatment of HL and aggressive NHL Post-treatment FDG-PET is highly predictive of PFS and OS in HL and (aggresive) NHL

30 Early/interim PET for response adapted therapy An early reliable prediction of response to therapy may separate high-risk poor prognosis patients from those with good prognosis. For the high-risk group, a more intensive regimen can be started at an earlier point For the good prognosis group, harmful side effects by unnecessary treatment might be reduced with a less intensive and less toxic regimen.

31 Early response evaluation Predictor of treatment outcome Several studies, in Hodgkin lymphoma and in aggressive non Hodgkin lymphoma, have showed that an early FDG-PET scan (ipet), after 1 to 3 cycles of chemotherapy, is a strong predictor of treatment outcome outperforming IPS and IPI. However, no conclusive evidence that changing treatment according to ipet improves outcome (ongoing trials) and it is not recommended to do so. ipet seems less predictive for response with immunochemotherapy (end-treatment PET is better)

32 Early/interim PET for response adapted therapy Size reduction is not an accurate predictor of outcome. In HL tumor cells make up a very small fraction of the tumor (surrounded by reactive). Shrinking depends on the cell type and the patient s immune system, and takes time CT cannot predict outcome

33 Early/interim PET for response adapted therapy. From: Baba S et al. Impact of FDG-PET/CT in the management of lymphoma. Ann Nucl Med (2011) 25: NPV of interim PET is over 80% in aggressive NHL and 90% in HL. Because of the high NPV value and significant difference of outcome between PET-positive and -negative patients, interim FDG-PET is increasingly being used in the sense of risk-adapted therapy

34 Early/interim PET for response adapted therapy Conclusions The prognostic power of negative FDG is outstanding, and there is a consensus that FDG- PET provides an accurate prognosis in patients who have received 1 4 cycles of chemotherapy or immunochemotherapy. However, close attention should be paid when evaluating the patient prognosis using a positive interim FDG-PET scan by visual assessment, because the PPVs of such scans are limited.

35 Problems/controversies Problems/controversies: There is no consensus on criteria able to early identify good and bad responders to treatment. Visual interpretation using the International Harmonization Project (IHP) criteria, primarily established for end of treatment evaluation

36 Response evaluation - criteria The IHP criteria (2007) specified that uptake should be less than or equivalent to the mediastinal blood pool for lesions 2 cm or larger, or the adjacent background for smaller lesions to define metabolic response at the end-of-treatment. In early response assessment, treatment is incomplete so the emphasis is on the degree of response and a continuous scale is desirable rather than positive/negative response categories.

37 Response evaluation - IHP The International Harmonization Project (IHP) Interpretation Criteria 2007 *. PET-negative residual mass (definition): FDG uptake lower than the local background for lesions less than 2 cm or or lower than mediastinal blood pool for lesions equal or greater than 2 cm Use: Widely accepted for end-of-treatment evaluation, but generate falsepositive interpretations when applied to interim evaluation because minimal residual uptake (MRU) should probably be tolerated after a few cycles of chemotherapy. The necessity for measuring residual node size on CT adds inter observer variability to the existing variability of PET image Interpretation *Juweid et al. JCO 2007

38 Response evaluation - general Early attempts to address this used three response groups (negative, minimal residual uptake [MRU] and positive Further refinement led to the development of a five-point scale (5PS, Deauville) which better represents different grades of uptake

39 Response criteria In an effort to harmonize interim PET interpretation criteria in the PET/CTera The First International Workshop on Interim PET in Lymphoma was held in Deauville in Deauville, France International Harmonization Project 2007 London criteria 2010 Gallamini criteria 2007 Deauville criteria 2010, 2011 October 2012 in Menton

40 Moderately: Uptake greater than the maximum SUV in a large region of normal liver Markedly: Uptake 2-3 times greater than the Maximum SUV in a large region of normal liver It is acknowledged that mean liver SUV may be less I nfluenced by image noise than maximum SUV, but reproducibility is more dependent on standardising t he location and size of the region of interest

41 Interpretation of 5PS (Deauville) 1. no uptake 2. uptake mediastinum 3. uptake > mediastinum but liver 4. uptake moderately higher than liver 5. uptake markedly higher than liver and/or new lesions X new areas of uptake unlikely to be related to lymphoma Moderately: Uptake greater than the maximum SUV in a large region of normal liver Markedly: Uptake 2-3 times greater than the Maximum SUV in a large region of normal liver Score 1-2: CMR Score 3: ipet: Probably CMR in patients receiving standard treatment End of treatment PET: good prognosis Score 4-5: Reduced uptake from baseline ipet: PMR End of treatment PET: residual metabolic disease Increased uptake from baseline No decrease in uptake from baseline New foci Treatment failue and/or progression

42 Why is Deauville better than IHP? The liver is a better reference background than the mediastinal blood pool or nearby background, because of its higher SUV level A residual mass with an FDG uptake higher than the liver background better differentiates from the background noise and has less risk to be attributed to a nonspecific uptake. Minimal residual uptake (MRU) corresponds to foci of low-grade uptake in an area of previously noted disease and is likely to represent inflammation, but smallvolume malignancy cannot not be excluded. In addition, the 5PS eliminates the reference to the size of the residual mass, which prevents different readers to compare the same residual uptake to different backgrounds, mainly when a residual tumor of about 2 cm is assessed. IHP is not recommended for early or mid-treatment response evaluation. Deauville is preferred. SUV is for research

43 The Deauville criteria clinical application Baseline Deauville 4 Deauville 1

44 Timing of treatmemt evaluation It is strongly recommended that a baseline scan is available comparison The scan is performed with either lower dose or diagnostic (ce). If the baseline cect demonstrates no relevant findings, then lower dose CT is sufficient for response assessment The time to scan Chemotherapy: as long as possible min 3 wks preferably 6-8 wks GCSF treatment : 2 weeks Radiotherapy: 3 months

45 Quantitative asessment Quantitative applications of FDG-PET are also recognised as objective tools for response monitoring accurate measurement relies on consistent methods for acquisition and processing and rigorous quality assurance of equipment for widespread application

46 Quantitative asessment SUV Standardized uptake value a widely used, simple PET quantifier SUV = CPET(T) / (Injected dose / body weight)

47 SUVs tumor metabolism underestimation of true activity in small tumors heterogeneous tumors time (after inj) dependent plasma glucose dependent Body weight, BSA, LBM Scanning parameters and PET-scanner Intraindividual variation in FDG uptake in serial PET-scans is low (CV 10%). Changes by more than 20% ( 1 SUV) is significant

48 Response evaluation - early Eur J Nucl Med Mol Imaging (2013) 40: Conclusion: Although the Deauville criteria are valid for assessing the prognostic value of early PET/CT in DLBCL, computation of the SUVmax leads to better performance and inter-observer reproducibility, and should be preferred when a baseline scan is available

49 Early response evaluation

50 Different criteria for interim PET in HL and DLBCL? Assumptions: In HL, neoplastic Reed Sternberg is 1% of the overall cellularity. The non neoplastic cellular compartment is switched-off very early by chemotherapy: known as metabolic CR. In NHL, the neoplastic cells is 90% of the total cell population and a progressive fraction of neoplastic cells are lysed by the chemotherapy. The percentage of the cell destruction is predictive of the final response to the chemotherapy. For these reasons, it is argued that a visual assessment seems preferable in HL, whereas a quantitative approach by SUVmax measurement seems more appropriate in DLBCL

51 Post treatment surveillance Routine long-term follow up is not recommended (subclinical disease). If transformation of Indolent NHL is suspected PET is recommended for biopsy guidance

52 Post treatment surveillance PET is now the standard of care for end-oftreatment response assessment in Hodgkin lymphoma and aggressive non-hodgkin lymphoma but not for surveillance. The Hodgkin lymphoma guideline explicitly states that surveillance PET should not be done because of the risk of false-positives, nor is PET recommended in the non-hodgkin lymphoma guideline

53 Post treatment surveillance JNM 2013,54;

54 Post treatment surveillance 6 lymphoma studies 2 prospective PET (Mantle cell and mixed) 4 retrospective PET/CT (2 Hodgkin, one non Hodgkin one mixed) Four were rated as quality B and 2 as quality C Quality B studies had some deficiencies in the criteria, but these deficiencies were considered unlikely to result in a major bias (retrospective studies start with a lower grade of B). Quality C studies had serious design or reporting deficiencies JNM 2013,54;

55 Tuesday, August 28, 2012 Session 5, 11:30-12:10 PET/CT in Lymphoma FDG-avidity: high (exceptions) Staging (nodal & extra nodal): yes Response evaluation: yes Early / interim (ipet) Post-treatment Evaluation criteria: IHP Deauville Change in SUV max Surveillance FDG-avidity is lower in indolent disease than in aggressive disease Upward stage migration in 10-40% Strong predictor of treatment outcome (HL, aggressive NHL) Standard care Not recommended 5PS recommended Seems better in NHL Not for routine Transformation biopsy

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